1. Field of the Invention
The present invention relates to an apparatus and a method for noninvasive measurement, with which glucose in a subject is noninvasively measured optically through a measurement probe.
2. Description of the Related Art
In several prior art methods, noninvasive (NI) measurement of glucose concentration in a subject is described. This measurement method generally includes the steps of: bringing an optical probe into contact with a body part; performing a series of optical measurements; and collecting a series of light signals. Subsequently, these light signals or derived optical parameters are mutually associated with blood glucose concentrations for the establishing a calibration relationship. A glucose concentration is determined by a subsequent measurement using the light signals measured at that time and the previously established calibration relationship.
The method for noninvasive (NI) measurement of glucose is classified into two broad categories: one is a method of tracking molecular properties; and the other is a method of tracking the effect of glucose on tissue properties. The method in the first category includes tracking intrinsic properties of glucose such as near-infrared (NIR) absorption coefficients, mid-infrared absorption coefficients, optical rotations, Raman shift band and NIR photoacoustic absorption. Such a method is based on an ability to detect glucose in a tissue or blood independently of other analytes of the body and also physiological conditions of the body. The method of the second type is based on the measurement of the effect of glucose on optical properties of tissue such as scattering coefficients of tissue, refractive index of interstitial fluid (ISF) or sound propagation in tissue.
The method of the first type of tracking the molecular properties of glucose faces a big problem because a signal which can be considered to be specific for glucose is extremely weak. Biological noise, a person-to-person difference, and measurement noise may drown out a small change in signal specific for glucose. In order to extract glucose-related information from a data set with noise, a multivariate analysis has been commonly used. The method of the second type of tracking the effect of glucose on tissue properties instead of the intrinsic molecular properties of glucose faces a big problem because of a nonspecific property of the change in parameters to be measured.
The method of both types of tracking the molecular properties of glucose and the effect of glucose on tissue properties ignores the physiological response of the body to a change in glucose concentration. This response can be seen in the form of a change in blood flow or temperature. Such a change in blood flow or temperature as a result of the physiological response of the body affects NIR light signals. The measurement by the method of both types also ignores the effect of the body-probe interaction on signals measured, and further, a specific time window for data collection from the initiation of the body-probe interaction is not defined.
Absorption Method:
Patent documents 1, 2, 3, 4, 5, 6, 7 and 8 describe a method in which glucose is measured by bringing an optical probe into contact with a body part and also reflection or transmission signals in near-infrared (NIR) region ranging from 600 to 1100 nm are measured. In general, a blood-containing body part (such as a finger) is illuminated with one or more light wavelengths, and one or more detectors detect the light passing through the body part. A glucose level is derived from the comparison of the reference spectrum of glucose and the background interference. These patents do not deal with the physiological response of the body to a change in glucose concentration, or the tissue-probe adaptation effect on the light signals measured.
In patent documents 9, 10 and 11, measurement of glucose NIR signals at a long wavelength ranging from 1000 to 1800 nm has been claimed. These patents disclose a method in which an extremely low signal is tried to be measured in the presence of biological noise which is much larger than the signal. The method of these patents does not provide temperature modulation at the measurement site, and these patents do not deal with the physiological response to a change in glucose concentration or the response of the body to the probe when the body and the probe interact with each other during the measurement.
Patent documents 12 to 19 disclose a method for NI measurement of glucose using NIR reflectance and transmittance measurement at a wavelength ranging from 1000 to 2000 nm. These patents do not deal with the physiological response of the body to glucose or problems of the probe-tissue interaction, or describe the application of temperature stimulation.
An example of the magnitude of NIR glucose intrinsic absorption signals is illustrated by the recently measured values of the molar extinction coefficient ε of glucose in water reported in the article in the journal (Non-patent document 1). The absorption ratio of glucose in water was determined to be 0.463 M−1 cm−1 at 1689 nm, 0.129 M−1 cm−1 at 2270 nm and 0.113 M−1 cm−1 at 2293 nm (here, M represents a molar concentration). These values of absorption ratios are much smaller than the ε value of NADH at 340 nm being 6.2×10+3 mol−1 cm−1, which is commonly used for the measurement of serum glucose values with an automated blood analyzer. When a 1 mm pathlength is used, a 10 mM glucose solution has 4.63×10−4 absorbance units at 1686 nm, and 1.29×10−4 absorbance units at 2257 nm. The 1 mm pathlength is longer than the pathlength encountered in the NIR diffuse reflectance measurement, and has a magnitude comparable to the pathlength in the localized reflectance measurement. The intrinsic extinction coefficient of glucose has a magnitude much lower at the higher overtone bands between 800 nm and 1300 nm than that at 2200 nm. The quantitative interpretation of data in this spectral range requires an extremely high sensitive detection system with a high signal to noise ratio and tight temperature modulation, and elimination of biological background noise source. Although IR absorption measurement of glucose has reasonable specificity in aqueous solutions, it faces a serious problem when attempted at the body sites of a subject.
The earliest report of use of measurement of NIR absorption and reflectance was reported in 1992 (Non-patent document 2), however, a commercially available device for noninvasive measurement of glucose by NIR has been unavailable so far.
Scattering Method:
Patent document 20 by Simonsen et al. and Patent document 21 by Gratton et al. disclose a method of measuring a scattering coefficient in deep tissue structures such as calf muscle and abdominal area. The geometric arrangement of a measurement probe, a distance between a light source and a detecting point, and the use of diffusion approximation in a light transport equation require light sampling at a depth of about several centimeters in a tissue.
A scattering method for NI measurement of glucose is described in the articles in the literatures of Non-patent documents 3, 4, and 5. In the method using the effect of glucose on the magnitude of a tissue scattering coefficient, a change in refractive index of interstitial fluid (ISF) which is resulted from a change in glucose concentration is tracked. The effect of a solute concentration on the refractive index of a solution is not specific for a given compound. A change in other soluble metabolite and electrolyte concentrations or tissue hydration affects the refractive index in the same manner as a change in glucose concentration. The reported clinical results have showed that there is no specificity and it is impossible to predict a glucose concentration (Non-patent document 6).
The effect of changing temperature on tissue scattering and absorption properties has been very interesting in noninvasive monitoring techniques. This has been reported in a few articles in journals. Please see Non-patent documents 7 and 8. The effect of temperature on the optical properties of the human skin has been reported in the articles in the journals of Non-patent documents 9, 10, 11 and 12. These published reports show a reversible linear change in scattering coefficient of the human skin after changing the temperature, and a more irreversible change in skin absorption coefficient after changing the temperature.
Thermal Radiation Method:
Other patents and patent application publications disclose a method which depends on IR radiation from a subject. In Patent documents 22 and 23 by Sterling et al., altered thermal IR radiation was used for NI measurement of glucose. The use of metabolic thermal radiation from a subject as means for glucose measurement has been disclosed in Patent documents 24 and 25 by Cho et al., and Patent document 26 (June, 2005) and Patent document 27 (June, 2005). A few experimental data have been disclosed in the articles in the journals: Non-patent documents 13 and 14. Cho et al. did not separate the circadian effect of the body which causes a temperature change from a change in glucose concentration which may cause a temperature change in a similar manner. Cho et al. did not take the skin-probe adaptation effect on the optical or thermal signals into consideration, or did not generate a temperature change that affects glucose metabolism.
Patent document 28 by Buchert and the article of the journal of Non-patent document 15 describe a method for NI measurement of glucose based on a spectral analysis of IR radiation from the tympanic membrane. Buchert and Malchoff et al. did not induce a temperature change for affecting glucose metabolism.
The use of a temperature change in combination with optical measurement with respect to a subject is described in other NI optical measurements. Patent documents 29, 30, 31, 32, 33 and 34 describe an oximeter probe having a heating element designed such that it is disposed against a body part. In Patent document 35, a glucose sensor which is brought to a specified temperature and in which a scattering coefficient μs′ is calculated is described and a glucose concentration is estimated from the effect on the refractive index of interstitial fluid (ISF). Patent document 35 does not disclose the calculation of oxygen consumption as a result of the physiological effect of glucose metabolism, or describe the use of temperature-enhanced glucose metabolism, or disclose the use of time window for reducing the tissue-probe adaptation effect on the measurement to the minimum.
Patent document 36 by Mills describes a method for measuring blood parameters at various temperatures based on the measurement of diffuse reflectance or transmission. Patent document 36 does not disclose the calculation of oxygen consumption as a result of the physiological effect of glucose metabolism, or describe the use of temperature-enhanced glucose metabolism, or take the time window for reducing the tissue-probe adaptation effect on the measurement to the minimum into consideration.
Although there are a variety of prior art and a large number of published patents in the past 10 years, however, any of the methods of noninvasive detection of glucose in a human tissue was not commercially successful. Accordingly, a method for noninvasive measurement of glucose in a subject which overcomes the problems of the signal magnitude and specificity, and without resorting to insertion of a probe or extraction of a sample has been still needed.
Further, several prior art methods for noninvasive (NI) quantification of the concentration of an analyte, particularly glucose in a subject generally includes the steps of: bringing a measurement probe into contact with a body part; performing a series of optical measurements; and collecting a set of light signals. These light signals or derived optical parameters calculated from the signals are mutually associated with blood glucose concentrations for establishing a calibration relationship. A glucose concentration is determined by a subsequent measurement using the light signals measured at that time and the previously established calibration relationship.
The method for noninvasive (NI) determination of glucose is classified into two broad categories: one is a method of tracking molecular properties; and the other is a method of tracking the effect of glucose on tissue properties. The method in the first category includes tracking intrinsic properties of glucose such as near-infrared (NIR) absorption coefficients, mid-infrared absorption coefficients, optical rotations, Raman shift band and NIR photoacoustic absorption. Such a method is based on an ability to detect glucose in a tissue or blood independently of other analytes of the body and also physiological conditions of the body. The method of the second type depend on the measurement of the effect of glucose on optical properties of tissue such as scattering coefficients of tissue, refractive index of interstitial fluid (ISF) or sound propagation in tissue.
The method of the first type of tracking the molecular properties of glucose encounters an extremely weak signal which can be considered to be specific for glucose. Biological noise, a person-to-person variation, and measurement noise may drown out a small change in the signal specific for glucose. In order to extract glucose-related information from a data set with noise, a multivariate analysis has been commonly used. The method of the second type of tracking the effect of glucose on tissue properties faces a big problem because of a nonspecific property of the change in refractive index calculated from the change in scattering coefficient.
In either type of methods, the intensity of the detected signal is extremely smaller than that of the biological and bodily interface noise. The variable probe-skin interaction which is attributable to the variation in the interface between a probe and the body, and a variable contact between a measurement probe and the skin due to the error of repositioning of the probe can have an effect on a measured signal which is larger than an effect on a change in glucose concentration.
The prior art method of both types of tracking the molecular properties of glucose and the effect of glucose on tissue properties ignores the effect of the body-probe interaction on the measured signal, and a method for reducing this effect is not described. As a result, a reference value of glucose is generally applied (fitted) to a signal adversely affected by an optical effect of an interaction between a probe and the skin or a probe and a body part.
Patent documents 37 to 44 describe a light absorption method for measuring reflection or transmission signals in near-infrared (NIR) region ranging from 600 to 1100 nm for measuring glucose by bringing a measurement probe into contact with a body part. In general, a blood-containing body part (such as a finger or a skin region of an arm) is illuminated with one or more wavelength lights, and one or more detectors detect the light passing through the body part or reflecting from the body part. A glucose level is derived from the comparison of the reference spectrum of glucose and the background interference. These patent documents do not deal with the tissue-probe adaptation effect on the light signals measured.
In Patent documents 45, 46 and 47, measurement of glucose NIR signals at a long wavelength ranging from 1000 to 1800 nm has been claimed. The method of these patent documents does not deal with a reaction of the skin with a measurement probe when the measurement probe interacts with the skin during measurement.
Patent documents 48, 49 and 50 transferred to Sensys Medical, Patent documents 51 and 52 transferred to Matsushita, and Patent documents 53, 54 and 55 transferred to Inlight Solutions disclose a method for NI quantification of glucose using measurement of NIR reflectance and transmission at a wavelength ranging from 1000 to 2000 nm. These patent documents do not deal with problems of the probe-tissue interaction, particularly adaptation of the skin to a probe and a variability of contact between the skin and a measurement probe.
Patent document 56 by Simonsen et al. and Patent document 57 by Gratton et al. disclose a method for measuring a bulk scattering coefficient in deep tissue structures such as calf muscle and abdominal area. The published clinical results show that it lacks specificity and glucose concentration cannot be predicted (Non-patent document 16). A drift (change) in the signal independent of glucose was observed, and it was larger than a change in scattering coefficient due to a change in glucose concentration in some cases.
In Patent document 56, a glucose sensor that is brought to a specified temperature is described and a bulk scattering coefficient is calculated, and a glucose concentration is estimated from the effect on the refractive index of interstitial fluid (ISF). Patent document 56 does not disclose a method for reducing the effect of tissue-probe adaptation on the measurement to the minimum.
Patent document 58 by Mills describes a method for measuring blood parameters at various temperatures based on the measurement of diffuse reflectance or transmission. Patent document 58 does not disclose a method for reducing the effect of tissue-probe adaptation on the measurement to the minimum.
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